Amyloidosis is a general term that describes a number of diseases characterized by extracellular deposition of protein fibrils, which form numerous “amyloid deposits,” which may occur in localized sites or systemically. The fibrillar composition of these deposits is an identifying characteristic for the various forms of amyloid disease. For example, intracerebral and cerebrovascular deposits composed primarily of fibrils of beta amyloid peptide (β-AP) are characteristic of Alzheimer's disease (both familial and sporadic forms), islet amyloid protein peptide (IAPP; amylin) is characteristic of the fibrils in pancreatic islet cell amyloid deposits associated with type II diabetes, and β2-microglobulin is a major component of amyloid deposits which form as a consequence of long term hemodialysis treatment. More recently, prion-associated diseases, such as Creutzfeld-Jacob disease, have also been recognized as amyloid diseases.
The various forms of disease have been divided into classes, mostly on the basis of whether or not the amyloidosis is associated with an underlying systemic illness. Thus, certain disorders are considered to be primary amyloidoses, in which there is no evidence for preexisting or coexisting disease. In general, primary amyloidoses of the disease are characterized by the presence of “amyloid light chain-type” (AL-type) protein fibrils, so named for the homology of the N-terminal region of the AL fibrils to the variable fragment of immunoglobulin light chain (kappa or lambda).
Secondary or “reactive” amyloidosis is characterized by deposition of AA type fibrils derived from serum amyloid A protein (ApoSSA). These forms of amyloidosis are characterized by an underlying chronic inflammatory or infectious disease state (e.g., rheumatoid arthritis, osteomyelitis, tuberculosis, leprosy).
characterized by an underlying chronic inflammatory or infectious disease state (e.g., rheumatoid arthritis, osteomyelitis, tuberculosis, leprosy).
Heredofamilial amyloidoses may have associated neuropathic, renal, or cardiovascular deposits of the ATTR transthyretin type. Other heredofamilial amyloidoses include other syndromes and may have different amyloid components (e.g., familial Mediterranean fever which is characterized by AA fibrils). Other forms of amyloidosis include local forms, characterized by focal, often tumor-like deposits that occur in isolated organs. Other amyloidoses are associated with aging, and are commonly characterized by plaque formation in the heart or brain. Also common are amyloid deposits associated with long term hemodialysis. These and other forms of amyloid disease are summarized in Table 1. (Tan, S. Y. and Pepys, Histopathology 25:403-414, 1994; Harrison's Handbook of Internal Medicine, 13th Ed., Isselbacher, K. J., et al, eds, McGraw-Hill, San Francisco, 1995).
TABLE 1Classification of Amyloid DiseasesAmyloidProtein/ProteinProteinPeptidePrecursorVariantsClinicalAASerum Amyloid AReactive (secondary)Protein (ApoSSA)Amyloidosis:Familial Mediterranean feverFamilial amyloidnephropathy with urticariaand deafness (Muckle-Wells syndrome)AASerum amyloid AReactive systemicproteinamyloidosis associated(ApoSSA)with systemicinflammatory diseasesALMonoclonalAk, A, (e.g.,Idiopathic (primary)immunoglobulin lightAkIII)Amyloidosis: myeloma orchains (kappa, lambda)macroglobulinemia-associated; systemicamyloidosis associatedwith immunocytedyscrasia; monoclonalgammopathy; occultdyscrasia; local nodularamyloidosis associatedwith chronic inflammatorydiseasesAHIgG (1(γ1))Aγ1Heavy chain amyloidosisassociated with severalimmunocyte dyscrasiasATTRTransthyretin (TTR)At least 30Familial amyloidknown pointpolyneuropathymutations(e.g., Met 30, Portuguese)ATTRTransthyretin (TTR)e.g., Met 111Familial amyloidcardiomyopathy(Danish)ATTRTransthyretin (TTR)Wild-type TTRSystemic senileor Ile 122amyloidosisAapoAIApoAIArg 26Familial amyloidpolyneuropathyAgelGelsolinAsn 187Familial amyloidosis(Finnish)AcysCystatin CGln 68Hereditary cerebralhemorrhage withamyloidosis (Icelandic)AβAmyloid β proteinVarious: GlnAlzheimer's diseaseprecursor (e.g. β-APP695)618,Down's syndromeHereditary cerebralhemorrhage amyloidosis(Dutch)Sporadic cerebral amyloidangiopathyInclusion body myositisAB2MBeta2 microglobulinAssociated with chronichemodialysisAcal(Pro)calcitonin(Pro)calcitoninMedullary carcinoma ofthyroidAANFAtrial natriuretic factorFocal Senile Amyloidoses:Isolated atrial amyloidAββ-amyloid precursorBrainproteinSVEPa—Seminal vesiclesAB2MBeta2 microglobulinProstateKeratinPrimary localizedcutaneous amyloid(macular, papular)PrPPrion precursor proteinScrapie proteinSporadic Creutzfeldt-Jacob(33-35 kDa cellular27-30 kDaDiseaseform)Kuru (transmissiblespongiformencephalopathies, priondiseases)AIAPPIslet amyloidIslets of Langerhanspolypeptide (IAPP)Diabetes type II,InsulinomaPeptidee.g., precalcitoninExocrine amyloidosis,hormones,associated withfragmentsAPUDomasaSeminal vesicle exocrine protein
Often, fibrils forming the bulk of an amyloid deposit are derived from one or more primary precursor proteins or peptides, and are usually associated with sulfated glycosaminoglycans. In addition, amyloid deposits may include minor proteins and peptides of various types, along with other components, such as proteoglycans, gangliosides and other sugars, as described in more detail in the sections that follow.
Currently, there are no specific, amyloid-directed treatments for any of the amyloid diseases. Where there is an underlying or associated disease state, therapy is directed towards decreasing the production of amyloidogenic protein by treating the underlying disease. This is exemplified by the treatment of tuberculosis with antibiotics, thereby reducing the mycobacterial load, resulting in a reduction of inflammation and in associated reduction of SSA protein. In the case of AL amyloid due to multiple myeloma, chemotherapy is administered to patients, causing a reduction in plasma cells and a lowering of myeloma immunoglobulin levels. As these levels decline, the AL amyloid may clear. Co-owned U.S. patent applications U.S. Ser. No. 09/201,430, filed Nov. 30, 1998 and U.S. Ser. No. 09/322,289, filed May 28, 1999 reveal that amyloid plaque burden associated with Alzheimer's disease can be greatly reduced (and prevented) by administration of agents which produce or confer an immune response directed at β-amyloid peptide (Aβ) and fragments thereof. It is the discovery of the present invention that induction of an immune response to various amyloid plaque components is effective in treating a broad range of amyloid diseases.